Advances in the Regulation of Mammalian Follicle-Stimulating Hormone Secretion

Abstract

Mammalian reproduction is mainly driven and regulated by the hypothalamic-pituitary-gonadal (HPG) axis. Follicle-stimulating hormone (FSH), which is synthesized and secreted by the anterior pituitary gland, is a key regulator that ultimately affects animal fertility. As a dimeric glycoprotein hormone, the biological specificity of FSH is mainly determined by the β subunit. As research techniques are being continuously innovated, studies are exploring the underlying molecular mechanism regulating the secretion of mammalian FSH. This article will review the current knowledge on the molecular mechanisms and signaling pathways systematically regulating FSH synthesis and will present the latest hypothesis about the nuclear cross-talk among the various endocrine-induced pathways for transcriptional regulation of the FSH β subunit. This article will provide novel ideas and potential targets for the improved use of FSH in livestock breeding and therapeutic development.

Keywords: animal reproduction; follicle-stimulating hormone; gonadotropin-releasing hormone; pituitary; signal transduction.

Figure 1

Schematic of known function non-coding RNAs in the post-transcriptional regulation of FSH synthesis. In gonadotroph, GnRH stimulates the synthesis of FSH by directly binding to its receptor GnRHR through several signaling pathways. Some miRNAs (miR-132, miR-212, miR-125b and miR-7) play a role in the gonadotropin pathways [127,131,132,133]. Several miRNAs (miR-186-5p, miR-433, miR-361-3p, miR-7 and miR-21-3p) have been identified to directly target the Fshb 3′UTR [125,126,127,134]. Furthermore, circAkap17b [135] and lncRNA-m433s1 [130] up-regulated Fshb as miR-7 and miR-433 sponge respectively. ceRNA: competing endogenous RNA; FOXO1: forkhead box O1; GnRH: gonadotropin-releasing hormone; GnRHR: gonadotropin-releasing hormone receptor; SIRT1: silent information regulator 1.

Figure 2

Schematic of classic signaling pathways activated by GnRH. The classic signaling pathways include the cAMP/PKA/CREB signaling pathway, PKC/MAPK signaling pathway and Ca²⁺/CaMK II signaling pathway [144,145,146,147,148,149,150,151]. AC: adenylate cyclase; AP-1: activator protein-1; ATP: adeosine triphosphate; CaMK II: calmodulin-dependent protein kinase II; cAMP: cyclic adenosine monophosphate; CREB: cAMP response element binding; DAG: diacylglycerol; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; Egr1: early growth response protein 1; ER: endoplasmic reticulum; ERK: extracellular regulated protein kinase; GnRH: gonadotropin-releasing hormone; GnRHR: gonadotropin-releasing hormone receptor; IP₃: inositol triphosphate; IP₃R: inositol triphosphate receptor; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MEK: MAPK/ERK kinase; MKK: mitogen-activated protein kinase kinase; NFAT: nuclear factor of activated T-cells; PKA: protein kinase A; PKC: protein kinase C; PLC: phospholipase C.